Dendritic cells are specialized accessory cells along with TGF-β for the differentiation of Foxp3+ CD4+ regulatory T cells from peripheral Foxp3- precursors
Dendritic cells are specialized accessory cells along with TGF-β for the differentiation of Foxp3+ CD4+ regulatory T cells from peripheral Foxp3- precursors
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DOI：
10.1182/blood-2007-05-088831
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发表时间：
2007-12-15
期刊：
影响因子：
20.3
通讯作者：
Steinman, Ralph M.
中科院分区：
文献类型：
--
作者：
Yamazaki, Sayuri;Bonito, Anthony J.;Steinman, Ralph M.
Foxp 3（+）CD 25（+）CD 4（+）调节性T细胞在胸腺中产生（天然T细胞），但也可以从外周Foxp 3（-）CD 4（+）前体（诱导或适应性T细胞）分化。我们评估了后者分化的抗原呈递细胞（APC）的要求。在加入转化生长因子（TGF）-β的情况下，未成熟和成熟的树突状细胞（DC）群体均从Foxp 3（-）前体诱导抗原特异性Foxp 3（+）T细胞。利用内源性TGF-β，来自肠相关肠系膜淋巴结的DC能够分化为FoXp 3（+）T细胞。脾DC比DC耗尽的APC更有效100倍用于诱导T细胞活化，并且需要低10倍剂量的肽抗原。白细胞介素-2（IL-2）是必需的，但可以由DC刺激的T细胞内源性提供，而不是其他APC。表达CD 80/CD 86共刺激分子的DC诱导所需的IL-2。DC诱导的Foxp 3（+）T淋巴细胞在6天内分裂6次，由CD 62 L和CD 103阳性和阴性形式组成。诱导的Foxp 3（+）T细胞在体外具有抑制作用，在体内阻断肿瘤免疫。这些结果表明，DC是专门分化功能性外周Foxp 3（+）T细胞，并帮助设置阶段，使用DC以抗原特异性方式主动抑制免疫应答。
Foxp3(+)CD25(+)CD4(+) regulatory T cells are produced in the thymus (natural T regs) but can also differentiate from peripheral Foxp3(-)CD4(+) precursors (induced or adaptive T regs). We assessed antigen presenting cell (APC) requirements for the latter differentiation. With added transforming growth factor (TGF)-beta, both immature and mature populations of dendritic cells (DCs) induced antigen-specific Foxp3(+) T regs from Foxp3(-) precursors. Using endogenous TGF-beta, DCs from gut-associated mesenteric lymph nodes were capable of differentiating FoXp3(+)T regs. Spleen DCs were 100-fold more potent than DC-depleted APCs for the induction of T regs and required 10-fold lower doses of peptide antigen. Interleukin-2 (IL-2) was essential, but could be provided endogenously by T cells stimulated by DCs, but not other APCs. The required IL-2 was induced by DCs that expressed CD80/ CD86 costimulatory molecules. The DC-induced Foxp3(+)T regs divided up to 6 times in 6 days and were comprised of CD62L and CD103 positive and negative forms. The induced Foxp3(+)T regs exerted suppression in vitro and blocked tumor immunity in vivo. These results indicate that DCs are specialized to differentiate functional peripheral Foxp3(+)T regs and help set the stage to use DCs to actively suppress the immune response in an antigen-specific manner.